Fz Rt

where F is the Faraday constant, R is the gas constant, T is absolute temperature and Z is the zeta potential of the surface (see Chapter 7). Thus, in terms of pH,

where Z is expressed in millivolts.

The secretion of acidic and basic substances in many parts of the gut wall is also a complicating factor in the application of the equations, as the local pH in the region of the microvilli of the small intestine will undoubtedly influence the absorption of weak electrolytes. A drug molecule in the bulk will diffuse towards the membrane surface and so meet different pH conditions from those in the bulk phase. Whether or not this influences the extent of absorption will depend on the pH changes and the pKa of the drug in question. The negative charge on the membrane will attract small cations towards the surface and small anions will be repelled; one might thus expect some selectivity in the absorption process. The existence of this 'microclimate' has been questioned, but experimental evidence for its existence has been forthcoming from the use of microelectrodes, which revealed the existence of a layer on the (rat) jejunum with a pH of 5.5 when the pH of the bathing buffer was 7.2. The existence of this more acid layer has also been demonstrated on the surface of the human intestine.

Other complications include convective water flow and unstirred layers, discussed here.

Convective water flow

The movement of water molecules into and out of the alimentary canal will affect the rate of passage of small molecules across the membrane. The reasons for water flow are the differences in osmotic pressure between blood and the contents of the lumen, and differences in hydrostatic pressure between lumen and perivascular tissue, resulting, for example, from muscular contractions. It can be appreciated that the absorption of water-soluble drugs will be increased if water flows from the lumen to the blood side across the mucosa, provided that drug and water are using the same route. Water movement is greatest within the jejunum.

It has been shown in animals that the absorption of lipid-soluble molecules is affected by solvent flow induced by addition of salts to the lumen.2 Absorption of benzoic acid, salicylic acid, benzyl alcohol and digi-toxin has been shown to be increased by efflux of water from the lumen and decreased by flow into the lumen (see Fig. 9.6). One likely

Figure 9.6 The dependence of salicylic acid absorption on the net water flux (positive sign: flow directed from the lumen and towards the blood) in the rat jejunal loop perfused with hypo-, iso- and hypertonic solutions at pH 6.2 and 2.2. The lines, mean values with 95% confidence limits (shaded areas), were calculated by means of the parameters determined by a kinetic model with the following constants: concentration of salicylic acid in the perfusion solution 32.3 ^mol dm03, wet tissue weight 0.453 g, perfusion rate 0.11 cm3 min01, intestinal blood flow 0.945 at pH 6.2 and 0.968 cm3 min01 at pH 2.2.

Reproduced from reference 2.

Figure 9.6 The dependence of salicylic acid absorption on the net water flux (positive sign: flow directed from the lumen and towards the blood) in the rat jejunal loop perfused with hypo-, iso- and hypertonic solutions at pH 6.2 and 2.2. The lines, mean values with 95% confidence limits (shaded areas), were calculated by means of the parameters determined by a kinetic model with the following constants: concentration of salicylic acid in the perfusion solution 32.3 ^mol dm03, wet tissue weight 0.453 g, perfusion rate 0.11 cm3 min01, intestinal blood flow 0.945 at pH 6.2 and 0.968 cm3 min01 at pH 2.2.

Reproduced from reference 2.

explanation is that when water flows from the lumen the drug becomes concentrated and drug absorption is increased because of the more advantageous concentration gradient. Suggestions that water flow affects the 'unstirred' layers close to the membrane may also be valid in interpreting these data.

Unstirred water layers

A layer of relatively unstirred water lies adjacent to all biological membranes. The boundary between the bulk water and this unstirred layer is indistinct but, nevertheless, it has a real thickness. During absorption, drug molecules must diffuse across this layer and then on through the lipid layer. The overall rate of transfer is the result of the resistance in both water layer and lipid layer. The flux, J, for a substance across the unstirred layer is given by the expression